DESCRIPTION: The high prevalence of obesity in African-American (AA) women is of public health importance since AA women suffer higher mortality from cardiovascular and renal diseases than do white (W) women. The reason for their marked susceptibility to obesity remains poorly understood though it is now known that AA women manifest lower resting energy expenditure (REE) than W women. We propose a multi-pronged metabolic and genetic epidemiologic study to examine two candidate genes (UCP3 and b3AR) implicated in energy metabolism which have yet to be investigated in this high risk group. This application builds upon the findings from our previous study of a biracial cohort of 150 young women aged 19-21. We showed that REE (adjusted for fat mass and fat-free mass) in AA women was consistently lower than W by about 78 kcal/day across the entire range of adiposity. Further, REE was lower for those AA women homozygous for the C allele of UCP3 (exon 5). However, due to the relative rarity of the C allele among AA, our sample size of 5 AA homozygous for C allele yielded only a weak association, p=0.05. We propose to screen 600 AA girls, aged 12-15 years, using buccal swabs as a non-invasive method of obtaining DNA, to determine their UCP3 genotypes as well as b3AR genotypes. We will recruit 211 girls, selected based on their UCP3 genotype, for measurements of REE and body composition (using DEXA) in a controlled setting of the Clinical Research Center at the Cincinnati Children's Hospital. We will examine variation in REE across the genotypes of UCP3 with a large sample to corroborate our previous finding. The proposed 2x3 design will allow us to examine whether the effects associated with UCP3 variation are due to the UCP3 locus alone or due to the additive effect or interaction between UCP3 and b3AR. This has not been considered before. Our study will help to better understand the relationship between variation in two important candidate genes for energy metabolism, UCP3 and b3AR, and inter-individual variation in the levels of REE in this very high risk (for obesity) population. This application also builds on a well-established collaborative relationship between the PI and the researchers at the Cincinnati Children's Hospital and also with Dr. Ferrell's Human Genetics Laboratory at the University of Pittsburgh. Thus, information obtained from the proposed study should increase our understanding of the complex interrelationship between ethnicity, genetics, energy metabolism, and obesity development. This, in turn, should help advance our quest for "thrifty" genes, since parsimonious energy expenditure may be the main phenotypic manifestation of such a genotype.